Covid-19 vaccination reported side effects and hesitancy among the Syrian population: a cross-sectional study

Abstract Introduction Studying post-vaccination side effects and identifying the reasons behind low vaccine uptake are pivotal for overcoming the pandemic. Methods This cross-sectional study was distributed through social media platforms and face-to-face interviews. Data from vaccinated and unvaccinated participants were collected and analyzed using the chi-square test, multivariable logistic regression to detect factors associated with side effects and severe side effects. Results Of the 3509 participants included, 1672(47.6%) were vaccinated. The most common reason for not taking the vaccine was concerns about the vaccine’s side effects 815(44.4). The majority of symptoms were mild 788(47.1%), followed by moderate 374(22.3%), and severe 144(8.6%). The most common symptoms were tiredness 1028(61.5%), pain at the injection site 933(55.8%), and low-grade fever 684(40.9%). Multivariable logistic regression analysis revealed that <40 years (vs. ≥40; OR: 2.113, p-value = 0.008), females (vs. males; OR: 2.245, p-value< .001), did not receive influenza shot last year (vs. did receive Influenza shot last year OR: 1.697, p-value = 0.041), AstraZeneca (vs. other vaccine brands; OR: 2.799, p-value< .001), co-morbidities (vs. no co-morbidities; OR: 1.993, p-value = 0.008), and diabetes mellitus (vs. no diabetes mellitus; OR: 2.788, p-value = 0.007) were associated with severe post-vaccine side effects. Serious side effects reported were blood clots 5(0.3%), thrombocytopenia 2(0.1%), anaphylaxis 1(0.1%), seizures 1(0.1%), and cardiac infarction 1(0.1%). Conclusion Our study revealed that most side effects reported were mild in severity and self-limiting. Increasing the public’s awareness of the nature of the vaccine’s side effects would reduce the misinformation and improve the public’s trust in vaccines. Larger studies to evaluate rare and serious adverse events and long-term side effects are needed, so people can have sufficient information and understanding before making an informed consent which is essential for vaccination.


Introduction
March 2020, the novel coronavirus disease of 2019 (covid-19) was announced a pandemic by the World health Organization (WhO), only four months after the first known case of covid-19, reported in china [1]. the pandemic spread has been rapid and heterogeneous causing one of the greatest global humanitarian crises in recorded history. the vigilance around personal protective measures including wearing face masks, maintaining interpersonal 2-meter distance, avoiding mass gatherings, washing hands, and quarantine have slowly eased off.
although such measures might have mitigated the spread and thus saved lives, sustaining these measures in the long term must be balanced against the various health, social, and economic aspects [2]. therefore, vaccines remain the only solution for this never-ending crisis, triggering a massive global effort [3], as leading pharmaceutical companies and scientists were in a race against time to develop and test the first effective vaccine. several vaccines have been approved for emergency or full use by WhO: Pfizer-BioNtech, Oxford-astraZeneca, sinopharm BiBP, Moderna, Janssen, coronaVac, covaxin, Novavax, and convidecia. Other vaccines are under assessment by the WhO: sputnik V, sinopharm WiBP, abdala, Zifivax, corbevax, V, cOViran Barekat, sanofi-GsK, and scB-2019 [4]. immunization with the currently approved vaccines remains the only way to protect oneself against cOViD-19, especially when there is no clear global consensus on the treatment guidinclusionnes for covid-19. today 2.7 billion people have yet to receive their first vaccine dose against covid-19 [5]. Most of the unvaccinated live in lower-middle-income and low-income countries [5]. in syria, only 9.3% of the population is fully vaccinated [6], despite the total number of vaccines delivered to syria by the covid- 19 Vaccines Global access (cOVaX) being sufficient to cover 39% of the population [7]. syria received its first batch of covid-19 vaccines on 21april 2021, delivered by cOVaX [8]. the WhO supported the operating costs of vaccine administration, and vaccines are now available in 962 fixed sites: 39 hospitals, and 923 primary healthcare centres [7]. the vaccines currently available in syria are Pfizer-BioNtech, astraZeneca, sinopharm, Moderna, Janssen, sputnick light, sputnick v, and sinovac.
although the efficacy and safety of the approved vaccines have been shown to be promising by many prestigious organizations [9,10], information on the long-term side effects and safety in literature remains scant. headache, fever, fatigue, and pain at the site of injection were the most abundantly reported side effects of the covid-19 vaccine, with the side effect severity ranging between mild and moderate [11,12,13]. serious vaccine complications, despite the rarity, include blood clots after the first dose of the astraZeneca vaccine [11]. this dangerous complication has negatively impacted the acceptance of vaccines and disseminated fear of covid-19 vaccines. Despite covid-19 infecting over half a billion and killing millions [14], the public's lost confidence in vaccines safety and efficacy remains the main reason behind low vaccination rates [15,16]. the culprit, social media is negatively affecting the users' views and intentions to enrol in the uptake of the vaccine [17,18]. For these reasons, post-vaccination surveillance of the vaccines' side effects and reasons behind the stigma of vaccines has become an area of interest.
Our study aims to assess covid-19 vaccine uptake, self-reported vaccine side effects and the reasons for not taking the vaccine among syrians more than a year after the introduction of vaccines in syria. the objectives of this study are to identify factors associated with covid-19 vaccine side effects and severe side effects.

Study design and instrument
a cross-sectional study was carried out between 13 april 28 and May 2022, using convenience sampling strategy. a literature review was conducted to find related research on the topic of the study using relevant keywords (covid-19 vaccines, side effects, syria, and worldwide). after an extensive review, the survey was created by the authors according to the information published by the centres for Disease control and Prevention (cDc) [19]. We piloted the questionnaire to assess the clarity, acceptability, and relevance of the survey on 30 volunteers. these volunteers were happy with the questionnaire and were excluded from the final sample to avoid bias. the survey was displayed using Google Forms and distributed by the data collection group through social media apps (Facebook, telegram, Whatsapp, and instagram). to lower non-response bias, graphics interchange format (GiF) and posts were adapted to appeal to each social group. the questions were short multiple choice questions that required no typing. authors interacted with the participants online and viewers were allowed to comment on the link to increase the survey's popularity. Face-to-face interviews were also conducted with people in hospitals and on the streets. the inclusion criteria for this study were: syrian citizens (residing in syria or a syrian who took the vaccine outside syria), aged ≥ 16 years, willing to participate in the study, willing to complete the survey, and willing to provide informed consent. all other respondents not fulfilling the eligibility criteria were excluded from the study. inability of the participants to complete any section or give contradictory answers rendered the response as incomplete and was then removed from the statistical analysis during validation of the responses. the time needed to complete the survey was 5 min. a brief description of the study was given before the participants and/or their legal guardian(s) provided informed consent. all participants were informed that their responses will remain confidential and will only be used for scientific purposes. the survey included three parts, the first part contained questions on demographic features including age, gender, health status, history of known allergy, history of seasonal influenza shot, smoking history, and history of covid-19 infection. confirmation of covid-19 infection by polymerase chain reaction (PcR) was not required in this question. Previous studies found that self-reporting of covid-19 related symptoms are adequate predictors of covid-19 infection [20,21]. the second part had two options depending on whether the participant was vaccinated or not. Participants that did not take the vaccine were only asked for the reasons behind this, and then the survey would automatically end. For those that did take the vaccine, information gathered included the vaccine brand, number of doses received (sputnik light, and Johnson and Johnson are single dose vaccines), vaccination dates, self-reported side effects post-vaccination, symptom severity (self-rated with the options mild, moderate, and severe), onset of symptoms, duration of symptoms, use of painkillers, need for medical assistance, serious adverse events, and history and date of post-vaccination covid-19 infection. We also asked the participants about the symptoms that lasted more than two weeks post-vaccination. a sample size calculator (website: https://www.surveysystem.com/sscalc.htm) was used to calculate the sample size of 2401 participants based on a confidence interval of 2%, and a confidence level of 95%, for a population of 18284423.

Statistical analysis
the data was collected via Google Forms and were analyzed by entering the data in the statistical package for the social sciences (sPss) software version 25. Descriptive statistics were used to express the socio-demographic features of the study sample. Pearson chi-square test was performed to evaluate the association between categorical variables. all p-values < 0.05 were considered statistically significant. a multivariable logistic regression model was carried out to detect factors associated with side effects (vs. no side effects), the selected factors included age (<40 vs ≥40), gender (females vs males), smoking history (smoker vs non-smoker), occupation (healthcare worker vs non healthcare worker), seasonal influenza shot (received it vs did not receive it), vaccine brand (Oxford-astraZenecaa vs other vaccine brands, sputnik light vs other vaccine brands, and Pfizer-BioNtech vs other vaccine brands), history of covid-19 infection (positive history vs no history of covid-19 infection before vaccination), and co-morbidities (yes vs no). these selected factors entered into the model concurrently. the second multivariable logistic regression model was developed to identify factors associated with severe adverse effects (vs no, mild, and moderate side effects). the selected factors included age (<40 vs ≥40), gender (females vs males), smoking history (smoker vs non-smoker), occupation (healthcare worker vs non healthcare worker), seasonal influenza shot (received it vs did not receive it), vaccine brand (Oxford-astraZenecaa vs other vaccine brands, sputnik light vs other vaccine brands, and Pfizer-BioNtech vs other vaccine brands), history of covid-19 infection (positive history vs no history of covid-19 infection before vaccination), co-morbidities (yes vs no), diabetes mellitus (vs no diabetes mellitus), and hypertension (vs no hypertension).

Demographic characteristics by vaccination status and severity of side effects
Of 3523 total participants who completed the survey, 14 participants who refused to be included in the study were excluded (completion rate = 99.6% the 1837 unvaccinated participants reported the following reasons for not taking the vaccine: concern about the vaccines side effects 815 (44.4%), unconvinced of the vaccine benefits 762 (41.5%), will not contract covid-19 as previously contracted the virus 400 (21.8%), medical exemption 94 (5.1%), and vaccine unavailability 84 (4.6%).
comparing covid-19 vaccines by type of formulation (mRNa, inactivated, and viral-vector), showed that viral-vector vaccines were associated with a higher percentage of side effects 905 (81.8%) compared with m-RNa vaccines 250 (75.3%) and inactivated vaccines which were associated with lowest post vaccination side effects 151(64.8%) (p-value < .001). Viral-vector vaccines were also associated with higher percentage of severe side effects and use of painkillers 111 (10.0%) and 720 (65.0%) respectively compared to other types of formation (p-value = < 0.001). the highest reported covid-19 reinfection rate after the first dose and the second dose were among inactivated vaccines 23 (9.9%) and 26 (11.2%) retrospectively (p-value = 0.013) (table 2).

Discussion
Multiple vaccines have been developed during the past two years; these vaccines must be available, safe, and effective [22], with the aim to decrease the death and infection rates. Vaccine hesitancy represents a big obstacle despite all the efforts to counter the stigma [23]. Regarding vaccine status in syria, vaccine hesitancy is reducing the vaccination prevalence among the population. in our study 47.6% of participants were vaccinated, much higher than the actual vaccination rate reported in the country (9.3%) [6]. the reason for this difference may be due to unreported bias, unvaccinated individuals refuse to express their opinion in a questionnaire distributed by healthcare providers due to medical mistrust of the medical system and conspiracy theories [24]. a staggering 44.4% of unvaccinated participants reported that they were concerned about the vaccine's side effects. several studies in the United Kingdom and the United states of america showed that the main cause of vaccine hesitancy was concern about the side effects of the vaccines [25,26]. Despite, implementing various strategies to scale up vaccination campaigns and conduct vaccination at government institutions, universities, and schools, 4.6% of participants mentioned that they would like to take the vaccine, but the vaccine was not available. syrians can receive the vaccine whether or not they are pre-registered through an online platform [7]. Our study showed that vaccine hesitancy was higher among rural areas, and this was consistent with previous syrian studies [27,28]. a possible cause of this is the misunderstanding and myths regarding covid-19 vaccines and conspiracy beliefs, which is more common in the syrian countryside. Furthermore, we found that participants with a history of chronic co-morbidities or with known allergies were unwilling to get vaccinated. the fear of the vaccine side effects among those groups can be attributed to misinformation about covid-19 vaccines in low-income countries [29]. Participants aged 30 to 59 were linked to the unvaccinated group. a study from Jordan indicated that the older age groups (>35 years old) were less likely to take the covid-19 vaccines compared to younger age groups [30]. On the other hand, our data revealed higher vaccine acceptance among healthcare workers (hcW). in syria, hcW were the first to receive priority access to vaccines [28]. hcW are also aware of the importance of vaccination to help protect them during occupational exposure and to prevent the spread of the disease among patients and the community [31]. also, participants who received the influenza shot last year were linked to the vaccinated group and this was coherent with another study conducted in Jordan [30].
Regarding vaccinated participants, 78.1% were symptomatic after receiving a covid-19 vaccine. the most common symptoms according to our results were tiredness and fatigue, pain at the injection site, low-grade fever, headache, and muscle pain. this was consistent with previous studies conducted in saudi arabia, iraq, and the czech Republic [32][33][34]. the symptoms were most frequently reported within 12 to 24 h after vaccination and lasted mainly one day. this result was in line with a study conducted in the czech Republic and the United Kingdom [34,35]. the overwhelming majority of symptoms were mild and moderate in severity 64.6% and 28.6%, respectively. and this was consistent with what was announced by cDc and WhO [11,12]. Whereas, 8.6% of participants reported severe symptoms post-vaccination. a study from Jordan reported similar results [36]. however, an observational study in the United arab emirates and a cross-sectional study of healthcare workers in the United states of america showed various proportions of severe symptoms [13,37]. the majority of vaccinated participants used painkillers to alleviate post-vaccination discomfort; the highest proportion of those was among astraZeneca-Oxford (chadOx1) vaccine recipients. similar findings were observed in a study conducted in togo [38]. in comparison between the first dose and second dose, we observed that the side effects tend to be more severe after receiving the second dose, specifically astraZeneca-Oxford (chadOx1) and Pfizer BioNtech (BNt162b2). this was similar to previous studies which demonstrated that systematic and local side-effects were more common after receiving the second dose of covid-19 vaccines [35,39], and coherent with what was announced by cDc [14]. serious side effects after covid-19 vaccination are rare but can occur [11], in our study 3.9% of vaccinated participants reported they required medical consultation or hospital visit. this was similar to a study conducted in the United arab emirates [13]. serious side effects included blood clots, thrombocytopenia, anaphylaxis shock, seizures, and cardiac infarction. Despite the rarity of these serious side effects [40], and the lack of consensus on their association with vaccines [41], all of them have been previously mentioned in the medical literature [42][43][44][45][46]. in this study, people with a history of previous covid-19 infection had greater odds of post-vaccine side effects. this finding was similar to previous studies conducted in the United Kingdom and italy [44,47]. Participant characteristics of young age (<40 years), female sex, current smokers, history of chronic co-morbidities, astraZeneca-Oxford vaccine, and did not receive influenza shot last year had greater odds of post-vaccination side effects. these results were consistent with data from a large cohort study in the United states of america [39]. Furthermore, this study revealed that participants with younger age (<40 years), female sex, history of chronic co-morbidities, astraZeneca-Oxford vaccine, did not receive influenza shot last year also, and diabetes mellitus had greater odds of severe post-vaccination side effects. this finding was in line with previous studies conducted in togo and Mexico [38,48]. also, in this study participants with diabetes mellitus were more vulnerable to severe post-vaccination side effects. another study found that patients at greatest risk of developing side effects post-vaccination include those with a history of type-2 diabetes [49].
Pain at the injection site was the most frequent symptom, and the reason behind this might be due to delayed-onset injection site reactions [40,50], or what is called 'covid arm' , which is a delayed but harmless allergic reaction [51,52]. irregular heartbeats were reported by participants, although it is a rare prolonged side effect, a research study published in Nature Medicine looks at the possible link between different cardiac arrhythmias and covid-19 vaccination [53]. Menstrual abnormalities were self-reported as a prolonged symptom, and many studies have shown a possible link between the covid-19 vaccine and menstrual abnormalities [54,55]. syrian vaccination rates are extremely low by global standards [6], but the explosion of covid-19 infections has not been a problem which may be because the true scope of the covid-19 outbreak in syria is unknown due to limited testing capacity, underreporting, and lack of access to healthcare. however, a previous study showed that the increases in covid-19 are unrelated to levels of vaccination across 68 countries and 2947 counties in the United states [56]. the highest infection rate after the first dose of covid-19 vaccines was observed among the sinovac (coronavac) vaccine, which indicated that this vaccine provided poor immune protection against covid-19. a previous study in Malaysia found that coronavac effectiveness against covid-19 infection waned after 3-5 months of full vaccination [57]. sinopharm (BiBP) Vaccines had the highest infection rate after the second dose compared to all the other vaccine brands. a study from the Kingdom of Bahrain showed that compared to individuals vaccinated with astraZeneca, Pfizer-BioNtech, or sputnik V, those vaccinated with the sinopharm vaccine had a higher risk of post-vaccination infection [58].
the cross -vaccine comparison of our study showed that viral vector-based vaccines were associated with the more frequent side effects. Our results are consistent with the findings of a German cross-sectional study [59]. a study from algeria revealed that side effects are more prevalent among viral vector vaccines than inactivated virus vaccines [60], and this was adherent with our findings. in contrast, we found that inactivated virus vaccines were associated with lower adverse effects following vaccination. a systematic review study on the safety profile of covid-19 vaccines was showed that the low rates of local and systemic reactions were significantly lower among inactivated vaccines [61]. inactivated virus vaccine showed higher reinfection rates after vaccination and this finding were consistent with other previous studies [62,63].

Study limitations
the data deduced may not be generalized to the wider syrian population. credible published national data on the socio-demographic distribution of the population are unavailable to assess the representativeness of the study's sample. the authors used a convenience sampling strategy involving various social media platforms and convenient location interviews. syrians of an older age group represented a minority due to limited internet access. the elderly, the most vulnerable population, require vaccine protection; therefore, a study must be conducted to assess the vaccine uptake among this age group. as such, reaching out to these vulnerable populations must be prioritized. additionally, as this study is a self-reported survey, the responses may be subject to recall bias.

Conclusion
Most of the reported vaccine side effects were mild in severity and well-tolerated. however, age < 40 years, females, not receiving influenza shot, astraZeneca vaccine, co-morbidities, and diabetes mellitus were factors significantly associated with severe post-vaccination side effects. Viral vector-based vaccines were associated with the more frequent side effects. inactivated virus vaccines were associated with lower adverse effects and higher reinfection rates following vaccination. larger prospective studies to understand the causes of rare serious adverse events are needed to overcome vaccine hesitancy among people. the long-term adverse effects of vaccines will become more important in the future. however, these adverse effects may not be known unless the medical environment is favourable and access to medical care is easy.